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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 15 April 2010 (15.04.2010) WO 2010/040571 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/EP2009/00743 1 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 12 October 2009 (12.10.2009) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 08075816.2 10 October 2008 (10.10.2008) DE (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, FRAUNHOFER-GESELLSCHAFT ZUR ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, FORDERUNG DER ANGEWANDTEN TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, FORSCHUNG E.V. [DE/DE]; Hansastr. 27 c, 80686 ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Mϋnchen (DE). MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventors; and ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): BORLAK, Jurgen [DE/DE]; Arpke Str. 12 g, 31275 Lehrte OT Immensen Published: (DE). WELTMEIER, Fridjof [DE/DE]; Schwanenring — without international search report and to be republished 17, 30627 Hannover (DE). upon receipt of that report (Rule 48.2(gf) (74) Agent: BAUMBACH, F.; Robert-Rδssle-Strasse 10, — with sequence listing part of description (Rule 5.2(a)) 13 125 Berlin (DE). (54) Title: METHOD FOR A GENOME WIDE IDENTIFICATION OF EXPRESSION REGULATORY SEQUENCES AND USE OF GENES AND MOLECULES DERIVED THEREOF FOR THE DIAGNOSIS AND THERAPY OF METABOLIC AND/OR TUMOROUS DISEASES (57) Abstract: The invention is directed to the use of particular human genes, nucleic acids hybridizing to said genes, and gene products encoded thereby in the context of the diagnosis and/or therapy of metabolic and/or cancerous diseases, preferably of dia- betes mellitus and/or colorectal cancer, wherein the gene is selected from the group of the human chromosomal genes having at least one expression regulatory sequence according to matrix 1 ("de novo" HNF4αmatrix) in the range of 100000 nucleotides up- stream or downstream of their transcription start site in the human genome, and wherein the at least one expression regulatory se- quence according to matrix 1 is located within the chromosomal position specified by particular start and end sites. The invention further relates to a method for a genomewide identification of functional binding sites at specifically targeted DNA sequences with high resolution, wherein the method comprises, or preferably consists of, the steps of: a) chromatin immunoprecipitation and b) DNA-DNA hybridisation for the c) de novo identification of gene targets. Method for a genome wide identification of expression regulatory sequences and use of genes and molecules derived thereof for the diagnosis and therapy of metabolic and/or tumorous diseases The invention is directed to the use of particular human genes, nucleic acids hybridizing to said genes, and gene products encoded thereby in the context of the diagnosis and/or therapy of metabolic and/or cancerous diseases, preferably of diabetes mellitus and/or colorectal cancer. The invention further relates to a method for a genomewide identification of functional binding sites at specifically targeted DNA sequences with high resolution. Areas of application are the life sciences: biology, biochemistry, biotechnology, medicine and medical technology. Hepatic nuclear factor (HNF)-4 α is a member of the nuclear rece?ptor superfamily and known to be expressed in the liver, intestine, and pancreas (for review see Sladek et al. 2001; Schrem, 2002). Many reports have highlighted the importance of HNF4 α in the regulation of developmental processes in determining the hepatic phenotype, as well as the regulation of diverse metabolic pathways (e.g., glucose, cholesterol, and fatty acid metabolism) (Sladek et al., 1990; Jiang et al., 1995; Yamagata et al., 1996; Hadzopoulou-Cladaras et al., 1997). Therefore, HNF4 α is considered as a hepatic master regulatory protein, ln^contrast to other members of the nuclear receptor superfamily, HNF4α binds to its cognate DNA binding site as a homodimer (Jiang 1997; Sladek 1990). HNF4α is one of the best characterized transcription factors, and in the past some dozent direct binding sites were reported. The employment of ChlP-chip technologies demonstrated however that these are only the smallest fraction of the actual HNF4 α binding sites. Notably, Rada-lglesias et al. (2005) used custom made arrays with a low resolution encompasing the ENCODE regions, i. e. 1% of the genome, for ChlP-chip, and thus mapped 194 HNF4 α binding sites in the human hepatoma cell line HepG2. In another study binding sites in hepatocytes and pancreatic islets were mapped, but the approach focused on promoter regions only (Odom et al, 2004; Odom et al, 2006). Based on the findings published by Rada-lglesias et al. (2005) only a small fraction of HNF4 α binding sites are located in proximal promoter regions. As of today, a genome-wide footprinting of binding sites targeted by HNF4 α has not been reported. However, such a system would allow to identify the common rationale underlying the genome wide regulation processes induced by protein-DNA binding within the context of diseases caused by HNF4 α upregulation, such as adenocarcinomas of the colon may be, namely to identify specific regulatory sequences in the chromosomal genome which (a) bind to HNF4 α and (b) bind to proteins other than HNF4α, wherein said proteins bind to HNF4 α. The aim of the invention is thus to provide a method allowing a genome-wide high resolution map of binding sites relevant for the transcription regulation induced by HNF4 α, and the identification of human chromosomal genes having at least one specific regulatory sequence in their natural environment, and the use of said genes or gene products encoded thereby or of RNA hybridizing to said genes for the diagnosis and therapy of diseases, preferably of adenocarcinomas of the colon, caused by an deregulation of HNF4α To this end, the implementation of the actions and embodiments as described in the claims provides appropriate means to fulfill these demands in a satisfying manner. Thus, the invention in its different aspects and embodiments is implemented according to the claims. In the first aspect, the invention is directed to the use of a human gene, in particular the coding region thereof, or of a gene product encoded thereby or of an antibody directed against said gene product, or of DNA or RNA sequences hybridizing to said gene and coding for a polypeptide having the function of said gene product for the therapy and/or diagnosis of metabolic and/or cancerous diseases and/or to screen for and to identify drugs against metabolic and/or cancerous diseases, such as diabetes mellitus and/or colorectal cancer may be, wherein the gene is selected from the group of the human chromosomal genes having at least one expression regulatory sequence according to matrix 1 ("de novo" HNF4α matrix) in the range of 100000 nucleotides upstream or downstream of their transcription start site in the human genome, and wherein the at least one expression regulatory sequence according to matrix 1 is located within the chromosomal position specified by the start and end sites according to Tables 9-32 (chromosomes 1-22, X-, Y-chromosome, wherein Table 9 refers to the human chromosome 1, Table 10 refers to the human chromosome 2, etc., Table 30 refers to the human chromosome 22, Table 3 1 refers to the human X-chromosome, and Table 32 refers to the human Y-chromosome). The term "gene" according to the invention is directed to both the template strand, which refers to the sequence of the DNA that is copied during the synthesis of mRNA, and to the coding strand corresponding to the codons that are translated into a protein. The genes according to the invention and gene products encoded thereby can be easily derived from the common databases, as such are known to the person skilled in the art, wherein the UCSC Genome Database is particularly preferred: Karolchik D, Kuhn, RM, Baertsch R, Barber GP, Clawson H, Diekhans M, Giardine B, Harte RA, Hinrichs AS1 Hsu F, Miller W , Pedersen JS, Pohl A , Raney BJ, Rhead B, Rosenbloom KR Smith KE, Stanke M, Thakkapallayil A, Trumbower H , Wang T Zweig AS, Haussler D, Kent WJ. The UCSC Genome Browser Database: 2008 update. Nucleic Acids Res. 2008 Jan;36:D773, which is incorporated herein by reference. The term "coding region" according to the invention is directed to the portion of DNA or RNA that is transcribed into the mRNA, which then is translated into a protein. This does not include gene regions such as a recognition site, initiator sequence, or termination sequence.
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  • Genome-Wide Screening Identifies Genes and Biological Processes

    Genome-Wide Screening Identifies Genes and Biological Processes

    Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 10-12-2018 Genome-Wide Screening Identifies Genes and Biological Processes Implicated in Chemoresistance and Oncogene-Induced Apoptosis Tengyu Ko Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Cancer Biology Commons, Cell Biology Commons, and the Genomics Commons Recommended Citation Ko, Tengyu, "Genome-Wide Screening Identifies Genes and Biological Processes Implicated in Chemoresistance and Oncogene- Induced Apoptosis" (2018). LSU Doctoral Dissertations. 4715. https://digitalcommons.lsu.edu/gradschool_dissertations/4715 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. GENOME-WIDE SCREENING IDENTIFIES GENES AND BIOLOGICAL PROCESSES IMPLICATED IN CHEMORESISTANCE AND ONCOGENE- INDUCED APOPTOSIS A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical and Veterinary Medical Sciences through the Department of Comparative Biomedical Sciences by Tengyu Ko B.S., University of California, Santa Barbara 2010 December 2018 ACKNOWLEDGEMENTS I would like to express my sincerest gratitude to my major supervisor Dr. Shisheng Li for giving me the opportunity to join his team and the freedom to pursue projects. I appreciate all of his thoughts and efforts. Truly, none of these findings would be possible without his supervisions, supports, insightful discussions, and patience.